Throughout this disclosure, various publications are referenced by first author and date, within parenthesis, patent number or publication number. The complete bibliographic reference is given at the end of the application, immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference into this disclosure to more fully describe the state of the art to which this application pertains.
Resistance to antimicrobial agents is a recognized medical problem (Schaechter, et al., 1993; Murray, 1997). The problem was recognized early as penicillin resistance in staphylococci, and is now a recognized problem for the treatment of many bacterial infections, including essentially all nosocomial (hospital-acquired) bacterial infections (Bush, 1988; Steinberg, et al. 1996; Murray, 1997). Nosocomial infections occur in 5% of patients admitted to the hospital (about 2 million patients per year in the United States); they cause an estimated 20,000 deaths per year, and contribute to an additional 60,000 hospital deaths. It is estimated that nosocomial infections add about 7.5 million hospital days and $1 billion dollars in health care costs each year (Wilson, et al. 1991). The importance of antibiotic resistant bacteria has increased as many organisms, e.g., staphylococcus aureus, have developed resistance to several distinct antibiotics (the "multi-resistant" phenotype). The enzymes involved in drug resistance include the penicillinases, .beta.-lactamases, cephalosporinases, and others. These enzymes inactivate antibiotics by modifying them to inactive compounds. Resistance caused by enzymes also includes antibiotic modification by choramphenicol acetyltransferases and other aminoglycoside modifying enzymes (Murray, 1997). Other mechanisms which contribute to antibiotic resistance include drug permeability mutations, expression of transport proteins that actively extrude antibiotics from target organisms, and mutations in the drug targets themselves (Murray, 1997).